Regioselective chlorination of substituted phenyl rings is a desirable process step for the manufacture of many agrochemical and pharmaceutical products. Regioselective phenyl chlorination of 4,5-dihydro-1-phenyl-1H-1,2,4-triazole-5-ones in the 4-position is desirous for the synthesis of certain agrochemicals such as herbicides and insecticides. U.S. Pat. No. 4,980,480 describes numerous methods to prepare 4-halogenated phenyltriazole-5-ones but does not describe any specific use of reagents or solvents. U.S. Pat. No. 5,468,868 more specifically describes a two step sequence of chlorinations to first regioselectively introduce the 4-chloro group followed by the 2-chloro group in triazole-5-one compounds. The authors proceed to show that N,N-dimethylformamide (DMF) is the best solvent for the first step of 4-chloro substitution, showing the highest selectivity and yield. The authors further show that acetonitrile, although a cheaper and easier handled solvent, is not able to achieve the 90%+ regioselectivity for the 4-position, as required for intermediates of this kind to be commercially useful.
Further, nowhere in U.S. Pat No. 5,468,868 do these authors describe the potential use of mixed polar solvents leading to the preferred regioselective chlorination on the 4-position of the phenyl ring in a unpredictable ratio.
The literature also contains some reports of chlorination of phenyl rings in polar solvents such as N,N-dimethylformamide and acetonitrile. For example, R Adams et al in J. Am. Chem. Soc. 74, 3171, (1952) describes the chlorination of a benzenesulfonamide in DMF as the solvent. In another reference, Bull. Chem. Soc. Jap. 43 (10), 3318, (1970) the authors describe chiorinations in DMF or acetonitrile in which the ortho/para ratio is directly proportional to the dielectric constant of the solvent used.
This result is in direct contrast to the unexpected synergy observed when mixed solvents of high dielectric constant are added together in the certain ratios an herein described in this application.
Further, all of the references teach that DMF is the preferred solvent of choice for chlorinations of the 4-position of the phenyl ring in 4,5-dihydro-1-phenyl-1H-1,2,4-triazol-5-ones, which is in direct contrast to the results described and claimed herein, where increasing the DMF ratio past 50:50 with acetonitrile leads to a loss in regioselectivity, with 70:30 being the most preferred ratio of acetonitrile:DMF. Acetonitrile is less expensive than DMF and is easier to use and recover on a large scale. The mixed solvent described herein allows for a more commercially viable process with the desired enhanced regioselectivity that has not been described or inferred previously in the prior art.
The patents described above, and all patents discussed in this application, are hereby incorporated herein by reference in their entirety.